ethics of phase i oncology trials

Ethics of Phase I Ethics of Phase I Oncology TrialsOncology Trials

Manish Agrawal M.D., M.A.Manish Agrawal M.D., M.A.Department of Clinical BioethicsDepartment of Clinical Bioethics

Medical Oncology Clinical Medical Oncology Clinical Research UnitResearch Unit

National Institutes of HealthNational Institutes of Health

Phase I ResearchPhase I Research

Phase I research is research aimed Phase I research is research aimed at identifying the safety, toxicities at identifying the safety, toxicities and the appropriate dosing of a new and the appropriate dosing of a new drug or intervention for future drug or intervention for future efficacy studies (Phase II).efficacy studies (Phase II).

8 Requirements for 8 Requirements for Ethical ResearchEthical Research

1) 1) Collaborative partnershipCollaborative partnership2) Social value2) Social value3) Scientific validity3) Scientific validity4) Fair subject selection4) Fair subject selection5) 5) Favorable risk-benefit ratioFavorable risk-benefit ratio6) Independent review6) Independent review7) 7) Informed consentInformed consent8) Respect for human subjects8) Respect for human subjects

“ …“ …Phase I cancer drug research, for Phase I cancer drug research, for example, may not be performed on example, may not be performed on terminally ill subjects under these terminally ill subjects under these guidelines because there is no guidelines because there is no reasonable probability that it will reasonable probability that it will benefit the subjects.”benefit the subjects.”

-George Annas-George Annas

What the Critics SayWhat the Critics Say

Another CriticAnother Critic

““Informed consent documents make Informed consent documents make phase one studies sound like the phase one studies sound like the cure for your cancer”cure for your cancer”

LeRoy Walters LeRoy Walters (2000)(2000)

Ethical Criticisms of Ethical Criticisms of Phase I Oncology Phase I Oncology

ResearchResearch

Unfavorable Risk Benefit Unfavorable Risk Benefit RatioRatio

Informed Consent is Informed Consent is flawedflawed

Risk/Benefit RatioRisk/Benefit Ratio

Critics argue that the risks outweigh Critics argue that the risks outweigh the benefitsthe benefits

Some even argue that there are risks Some even argue that there are risks with no benefitswith no benefits

Decoster Decoster et al.et al. (1990) (1990)

Reviewing 211 trials involving 87 drugs Reviewing 211 trials involving 87 drugs and 6,639 patients between 1972-1987.and 6,639 patients between 1972-1987.

Complete ResponsesComplete Responses 0.3%0.3%

Partial ResponsesPartial Responses 4.2%4.2%

Toxic deathsToxic deaths 0.5%0.5%

What are the Benefits? What are the Benefits?

Estey Estey et al.et al. (1986) (1986)

Reviewing 187 trials involving 54 Reviewing 187 trials involving 54 drugs and 6,447 patients between drugs and 6,447 patients between 1974-1982.1974-1982.

Complete ResponsesComplete Responses 0.7%0.7%

Partial ResponsesPartial Responses 3.5%3.5%

What are the Benefits?What are the Benefits?

Toxic Death 0.5%Toxic Death 0.5%

Side effects- Neutropenia, hair loss, Side effects- Neutropenia, hair loss, neuropathy; severity and prevalence neuropathy; severity and prevalence is not quantifiedis not quantified

What are the Risks?What are the Risks?

Resource and time commitment from Resource and time commitment from patients and families; due to patients and families; due to frequent blood draws, radiological frequent blood draws, radiological evaluations, physician visits, evaluations, physician visits, biopsies etc.biopsies etc.

What are the Risks?What are the Risks?

Do the data as Do the data as discussed tell the discussed tell the

whole story?whole story?

Overall response rates may hide Overall response rates may hide important response data:important response data:

30% of the drugs from the meta-30% of the drugs from the meta-analyses had response rates over 5%analyses had response rates over 5%

Only 39% of the trials had no Only 39% of the trials had no objective responsesobjective responses

The meta-analyses only looked at The meta-analyses only looked at drugs from 1972-1987, the drugs drugs from 1972-1987, the drugs used now are better.used now are better.

A Second Look at the Meta-A Second Look at the Meta-analysesanalyses

Some remarkable therapeutic benefits Some remarkable therapeutic benefits in Phase I oncology trialsin Phase I oncology trials

Platinum had >50% response rate Platinum had >50% response rate in testicular cancerin testicular cancer

Gleevac had >90% response rate in Gleevac had >90% response rate in CMLCML

Some Notable Responses in Some Notable Responses in Phase I StudiesPhase I Studies

More Recent Data on More Recent Data on Risks/BenefitsRisks/Benefits

CTEP DatabaseCTEP Database

460 trials between 1991 and 2002460 trials between 1991 and 2002 10,402 patients for response 10,402 patients for response 11,935 patients for toxicity11,935 patients for toxicity

Risk-Benefit RatioRisk-Benefit Ratio

Yesterday’s Phase I is not today’s Yesterday’s Phase I is not today’s Phase I.Phase I.

Nature of Phase I oncology studies Nature of Phase I oncology studies have changed. They are no longer have changed. They are no longer only trials of “first in man” only trials of “first in man” chemotherapeutic agents.chemotherapeutic agents.


Review of CTEP Phase I data from 1991-Review of CTEP Phase I data from 1991-20022002

21% single investigational 21% single investigational chemotherapeutic agent.chemotherapeutic agent.

42% single investigational agent of any 42% single investigational agent of any kind.kind.

55% multiple investigational agents.55% multiple investigational agents.

45% include at least one proven agent.45% include at least one proven agent.


RRRR CRCR SDSD

Overall (460 Overall (460 agents)agents)

10.610.6%%

3.1%3.1% 34.134.1%%

1 Invest Chemo 1 Invest Chemo Agent Agent (20%)(20%)

4.4%4.4% 1.5%1.5% 40.840.8%%

Multiple Invest Multiple Invest Chemo Agent Chemo Agent ((2.6%)2.6%)

11.711.7%%

1.5%1.5% 27.527.5%%

Approved and Approved and Invest Chemo Invest Chemo Agents Agents (19%)(19%)

16.416.4%%

5.6%5.6% 31.331.3%%

1 Invest Signal 1 Invest Signal Transd. Agent Transd. Agent (11%)(11%)

3.2%3.2% 0.7%0.7% 39.339.3%%


DeathDeath Grade IV Grade IV ToxicityToxicity

Total (11,935)Total (11,935) 0.49%0.49% 14.3%14.3%

1 Invest Chemo 1 Invest Chemo Agent (2,621)Agent (2,621)

0.57%0.57% 15.0%15.0%

Approved and Approved and Invest Chemo Invest Chemo Agent (2,594)Agent (2,594)

0.77%0.77% 14.5%14.5%

1 Invest. Sign 1 Invest. Sign Transd (1,565)Transd (1,565)

0.19%0.19% 13.0%13.0%


CRCR PRPR SDSD DeathDeathss

3.8%3.8% 15.2%15.2% 23.0%23.0% 1.1%1.1%

•211 Phase I studies published in 2002

•6,008 participants evaluable for toxicity•5,362 participants evaluable for response

“…“…Patients do not seem to be harmed Patients do not seem to be harmed by their experience of participating in by their experience of participating in a phase I trial and may experience a phase I trial and may experience benefits, albeit not in terms of tumor benefits, albeit not in terms of tumor control” control”

Moore (2001) Moore (2001)

Benefits beyond Tumor Benefits beyond Tumor ResponsesResponses

If we are going to consider non-If we are going to consider non-medical risks, we should also medical risks, we should also consider non-medical benefits.consider non-medical benefits.

Benefits beyond Tumor Benefits beyond Tumor ResponsesResponses

Some data suggest that enrolling in Some data suggest that enrolling in Phase I research is beneficial to the Phase I research is beneficial to the quality-of-life of patients.quality-of-life of patients.

Patients in Phase I had stable Quality Patients in Phase I had stable Quality Of Life and performance status over 1 Of Life and performance status over 1 course of therapy whereas similar course of therapy whereas similar patients receiving supportive care had patients receiving supportive care had declines in QOL.declines in QOL.

Melink et al. (1992), Berdel et al. Melink et al. (1992), Berdel et al. (1988)(1988)

Other Benefits Beyond Other Benefits Beyond Tumor ResponseTumor Response

65% of research participants said they 65% of research participants said they believed they would receive believed they would receive psychological benefit from being in the psychological benefit from being in the phase I study.phase I study.

Structure and routine of trialsStructure and routine of trials Exercise some controlExercise some control Help others in the futureHelp others in the future

Daugherty et al. Daugherty et al. (2000) (2000)

Psychological ComfortPsychological Comfort

Risks may not be as bad as implied. Risks may not be as bad as implied.

0.7% risk of death for a terminally ill 0.7% risk of death for a terminally ill patient may not be very high.patient may not be very high.

It would be good to have more data It would be good to have more data on the risks of other side effects and on the risks of other side effects and morbidity rates.morbidity rates.

Summary of Risks Summary of Risks

Benefits may be greater than implied.Benefits may be greater than implied.

Many Phase I drugs trials have had Many Phase I drugs trials have had >15% response rates and at least 2 >15% response rates and at least 2 notable cases have provided notable cases have provided substantial therapeutic responses substantial therapeutic responses even cures.even cures.

QOL may be better on a Phase I trial QOL may be better on a Phase I trial than supportive care.than supportive care.

Summary of BenefitsSummary of Benefits

While the scientific objectives of While the scientific objectives of phase I oncology studies do not phase I oncology studies do not include patient benefit, there do include patient benefit, there do appear to be benefits.appear to be benefits.

Are the benefits enough to make Are the benefits enough to make risk/benefit ratio favorable?risk/benefit ratio favorable?

What do the Data Show?What do the Data Show?

Is the risk/benefit Is the risk/benefit ratio favorable or ratio favorable or

unfavorable?unfavorable?

Compare Results of Phase I Compare Results of Phase I Studies to FDA Approved Studies to FDA Approved

Chemotherapy Chemotherapy

High dose IL-2 for metastatic renal cellHigh dose IL-2 for metastatic renal cell

Complete ResponseComplete Response 5%5%

Partial ResponsePartial Response 9%9%

Median duration of response is 20 Median duration of response is 20 monthsmonths

Gemcitabine approved for improvement Gemcitabine approved for improvement in QOL for pancreatic cancer with in QOL for pancreatic cancer with response rate of only 5%response rate of only 5%

Compare Results of Phase I Compare Results of Phase I Studies to FDA Approved Studies to FDA Approved

ChemotherapyChemotherapy

Topotecan is approved with 10% Topotecan is approved with 10% response rate for ovarian cancer.response rate for ovarian cancer.

CPT-11 is approved for metastatic CPT-11 is approved for metastatic colon cancer on the basis of less colon cancer on the basis of less than 2 month prolongation of than 2 month prolongation of survivalsurvival

1% gain in absolute mortality for 4 1% gain in absolute mortality for 4 cycles of adjuvant chemotherapy for cycles of adjuvant chemotherapy for Stage I breast cancer.Stage I breast cancer.

Risk-Benefit Ratio Not Risk-Benefit Ratio Not Worse than Other Approved Worse than Other Approved

Therapy by FDA Therapy by FDA

The risk-benefit ratio for phase I The risk-benefit ratio for phase I oncology studies is clearly not oncology studies is clearly not worse than risk/benefit ratios used worse than risk/benefit ratios used by the FDA as a basis for approval by the FDA as a basis for approval of many chemotherapeutic agents.of many chemotherapeutic agents.

Who decides Who decides what is a what is a

favorable risk favorable risk benefit ratio?benefit ratio?

Who decides?Who decides?

Who currently decides a favorable Who currently decides a favorable risk-benefit ratio in research?risk-benefit ratio in research? InvestigatorsInvestigators BioethicistsBioethicists LawyersLawyers StatisticiansStatisticians PhysiciansPhysicians PolicymakersPolicymakers

Who Should Decide?Who Should Decide?

Should the people who are facing Should the people who are facing life-ending illness have some input life-ending illness have some input on whether a risk/benefit ratio is on whether a risk/benefit ratio is favorable for research studies?favorable for research studies?

Patients Have Different Patients Have Different Perceptions than Healthy Perceptions than Healthy

People People Substantial data demonstrates that Substantial data demonstrates that

patients facing serious illnesses make patients facing serious illnesses make very different assessments of their own very different assessments of their own condition and the risks they are willing to condition and the risks they are willing to confront compared to healthy individuals.confront compared to healthy individuals.

Even families, consistently overestimate Even families, consistently overestimate symptoms and underestimate patient symptoms and underestimate patient satisfaction and quality of lifesatisfaction and quality of life

Epstein (1989), Zweibel (1989)Epstein (1989), Zweibel (1989)

Patients need very small benefits to Patients need very small benefits to find cancer chemotherapy worthwhile.find cancer chemotherapy worthwhile.

Cancer patients only needed only 1% Cancer patients only needed only 1% chance of benefit to want an intensive chance of benefit to want an intensive chemotherapy regimen described with chemotherapy regimen described with many side effects.many side effects.

Nurses needed 50% chance, and Nurses needed 50% chance, and doctors needed a 10% chance, general doctors needed a 10% chance, general public needed 50% chance of benefit.public needed 50% chance of benefit.

Slevin Slevin et al.et al. 1990 1990

Patients Willing to Patients Willing to Undergo More Risk than Undergo More Risk than

Healthy PeopleHealthy People

A patient’s perspectiveA patient’s perspective

We who are struggling to escape cancer do We who are struggling to escape cancer do not, obviously, want to die of it. We do prefer not, obviously, want to die of it. We do prefer death in the struggle to life under cancer’s death in the struggle to life under cancer’s untender rule. The enemy is not pain or even untender rule. The enemy is not pain or even death, which will come for us in any death, which will come for us in any eventuality. The enemy is cancer, and we eventuality. The enemy is cancer, and we want it defeated and destroyed… This is how want it defeated and destroyed… This is how I wanted to die—not a suicide and not I wanted to die—not a suicide and not passively, but eagerly in the struggle.passively, but eagerly in the struggle.

George ZimmerGeorge Zimmer

Phase I patient University of ChicagoPhase I patient University of Chicago

Patient’s Perspective Patient’s Perspective Should be Taken into Should be Taken into

AccountAccount

Views of terminally ill cancer patients Views of terminally ill cancer patients should inform IRB determinations of should inform IRB determinations of favorable risk-benefit ratios for phase I favorable risk-benefit ratios for phase I oncology studies.oncology studies.

Including such patients might emphasize Including such patients might emphasize alternative study designs using higher alternative study designs using higher doses that increase toxicities but also doses that increase toxicities but also may increase the chance of benefitsmay increase the chance of benefits

Ethical Criticisms of Ethical Criticisms of Phase I Oncology Phase I Oncology

ResearchResearch

Unfavorable Risk Benefit Unfavorable Risk Benefit RatioRatio

Informed ConsentInformed Consent

DisclosureDisclosure Are Phase I informed consent Are Phase I informed consent

documents distortive?documents distortive?

UnderstandingUnderstanding Do terminally ill patients understand Do terminally ill patients understand

information about Phase I research?information about Phase I research?

VoluntarinessVoluntariness Are terminally ill patients able to Are terminally ill patients able to

choose freely?choose freely?

Invalid Informed ConsentInvalid Informed Consent


Problems with disclosure of Problems with disclosure of informationinformation

Physicians do not provide Physicians do not provide appropriate or accurate information. appropriate or accurate information.

Physicians stress and exaggerate the Physicians stress and exaggerate the benefits while minimizing the risks benefits while minimizing the risks of research participation.of research participation.


Problems with patient understanding.Problems with patient understanding.

Because they are terminally ill, patients cannot Because they are terminally ill, patients cannot understand the true objectives, benefits and risks understand the true objectives, benefits and risks of Phase I research. Their understanding is of Phase I research. Their understanding is clouded by their physical state and their hope for clouded by their physical state and their hope for a cure.a cure.

What clear thinking patient would opt to take What clear thinking patient would opt to take toxic drugs rather than receive palliative care toxic drugs rather than receive palliative care and comfort measures at the end of life?and comfort measures at the end of life?


Because terminally ill patients are Because terminally ill patients are not given proper information by not given proper information by their physicians, because they their physicians, because they cannot understand the information cannot understand the information they are given, and because they they are given, and because they are vulnerable, they cannot provide are vulnerable, they cannot provide valid informed consent.valid informed consent.

Informed ConsentInformed Consent

Can terminally ill patients provide Can terminally ill patients provide informed consent?informed consent?

Do Phase I researchers misinform Do Phase I researchers misinform patients?patients?

Do Phase I informed consent documents Do Phase I informed consent documents misinform?misinform?

Do terminally ill patients misunderstand Do terminally ill patients misunderstand information about Phase I research?information about Phase I research?

Are terminally ill patients under a Are terminally ill patients under a therapeutic misconception?therapeutic misconception?

Are terminally ill patients vulnerable?Are terminally ill patients vulnerable?

Do Phase I Do Phase I Researchers Researchers

Misinform Patients?Misinform Patients?

Do Physicians Do Physicians Misinform?Misinform?

Tomamichel Tomamichel et al.et al. (1995) (1995)

Recorded informed consent Recorded informed consent interactions for 32 patients.interactions for 32 patients.

Quantitative analysis indicated that 3 Quantitative analysis indicated that 3 major information points were major information points were communicated in almost 80% of cases. communicated in almost 80% of cases.

Use of indirect patient responses was Use of indirect patient responses was not as good.not as good.


Daugherty Daugherty et al.et al. (1995) (1995)

18 Phase I oncologists at U of 18 Phase I oncologists at U of ChicagoChicago

1-2 months added survival1-2 months added survival 10%10%Complete and partial responseComplete and partial response 15%15%Complete responseComplete response 1%1%

Life-threatening toxicityLife-threatening toxicity 10%10%DeathDeath 5%5%


Discussed with Discussed with PatientsPatients

PhysiciansPhysicians PatientsPatients

Possible side effectsPossible side effects 92%92% 78%78%

Possible risksPossible risks 92%92% 73%73%

Possible benefitsPossible benefits 90%90% 79%79%

Change in length of Change in length of lifelife

60%60% 29%29%

Meropol et al. (2003)48 physicians and 328 patients considering Phase I


Limited data suggests physicians do Limited data suggests physicians do not misinform patients and if they do not misinform patients and if they do misinform they tend to over-estimate misinform they tend to over-estimate risks more than benefits.risks more than benefits.

Do Phase I Informed Do Phase I Informed Consent Forms Consent Forms

Misinform?Misinform?

Informed Consent FormsInformed Consent Forms

Are Phase I informed consent forms Are Phase I informed consent forms distorted?distorted?

Do they over promise benefits?Do they over promise benefits?

Do they minimize risks?Do they minimize risks?

Do Forms Misinform?Do Forms Misinform?

Data from a review of 272 Phase I informed Data from a review of 272 Phase I informed consent documents from 1999.consent documents from 1999.

Only 29% of all Phase I oncology trials Only 29% of all Phase I oncology trials involve a previously untested drug in classic involve a previously untested drug in classic dose escalation design.dose escalation design.

40% of Phase I trails had a therapeutic 40% of Phase I trails had a therapeutic element. For instance, adding a new drug element. For instance, adding a new drug to a known effective drug.to a known effective drug.

Horng et al. (NEJM, 2002)Horng et al. (NEJM, 2002)


92% mention safety, dose 92% mention safety, dose determination, or toxicity as the determination, or toxicity as the purpose of the trial.purpose of the trial.

99% mention that the study is 99% mention that the study is research or an experiment with most research or an experiment with most of these being prominent or highly of these being prominent or highly prominent in the informed consent prominent in the informed consent form.form.


6% explicitly mention that the 6% explicitly mention that the research is not therapeutic.research is not therapeutic.

96% refer to the chemotherapy 96% refer to the chemotherapy agent as treatment or therapy.agent as treatment or therapy.


Median length of risk and benefit Median length of risk and benefit sectionssections

RiskRisk 35 lines35 lines

BenefitBenefit 4 lines4 lines

67% mention death as a possible risk67% mention death as a possible risk 33% mention death more than once33% mention death more than once 83% mention possibility of serious 83% mention possibility of serious

harmsharms


One of 272 forms mention benefits will One of 272 forms mention benefits will definitely accrue to subjects.definitely accrue to subjects.

Mention as possible benefitsMention as possible benefits

CureCure 5%5%Life prolongationLife prolongation 20%20%Tumor shrinkageTumor shrinkage 36%36%Generalizable knowledgeGeneralizable knowledge 68%68%


96% have separate alternatives section96% have separate alternatives section

Mention as alternativesMention as alternativesPalliative carePalliative care 56%56%Standard therapyStandard therapy 88%88%No treatmentNo treatment 65%65%Other experimental therapyOther experimental therapy 52%52%HospiceHospice <1%<1%


While the documents are not perfect and While the documents are not perfect and can be improved, it is hard to say that can be improved, it is hard to say that informed consent documents: informed consent documents:

Over promise benefits and minimize risksOver promise benefits and minimize risks

Disguise the nature of the trial or that it Disguise the nature of the trial or that it is researchis research

Promise curePromise cure

Do Patients with Do Patients with Advanced Cancer Advanced Cancer Misunderstand Misunderstand

Information about Information about Phase I Research?Phase I Research?

Do Patients Do Patients Misunderstand?Misunderstand?

Decoster Decoster et al.et al. (1990) (1990)

91% of patients on Phase I trials had 91% of patients on Phase I trials had prior therapy:prior therapy:

50% chemotherapy alone50% chemotherapy alone 25% chemotherapy and radiation 25% chemotherapy and radiation

therapytherapy 11% radiation therapy alone 11% radiation therapy alone



Recall signing consent formRecall signing consent form 100%100%Recall explanation of study as researchRecall explanation of study as research 98%98%Recall explanation of risks and side effects Recall explanation of risks and side effects 97% 97%Recall at least 1 specific side effectRecall at least 1 specific side effect 100%100%Felt well informedFelt well informed 96% 96%

Quality of the information transfer was associated with Quality of the information transfer was associated with higher education.higher education.


Joffe Joffe et al.et al. (2001) (2001)

Mailed survey of 207 Phase I, II, and III Mailed survey of 207 Phase I, II, and III cancer patients.cancer patients.

50 in Phase I studies, but not 50 in Phase I studies, but not distinguished in data analysis.distinguished in data analysis.



84% read the consent form carefully84% read the consent form carefully 87% had enough time to learn about 87% had enough time to learn about

the trialthe trial 93% sufficient time to ask questions93% sufficient time to ask questions 48% consent discussion last over 1 hour48% consent discussion last over 1 hour 44% consulted an outside physician44% consulted an outside physician


Almost all patients participating in Phase I Almost all patients participating in Phase I studies feel well informed and are satisfied studies feel well informed and are satisfied by the informed consent process:by the informed consent process:

StudyStudy # of Patients # of Patients % % SatisfiedSatisfied

DaughertyDaugherty 144144 96% 96%

Tomamichel Tomamichel 3131 96% 96%

JoffeJoffe 207 207 90% 90%

Do Terminally Ill Do Terminally Ill Patients have a Patients have a

Therapeutic Therapeutic Misconception about Misconception about

Phase I Trials?Phase I Trials?

Therapeutic Therapeutic Misconception?Misconception?

Study # Subjects Study # Subjects Results Results

Yoder Yoder 3737 70% to get best 70% to get best carecare

85% shrink tumor85% shrink tumor

Tomamichel Tomamichel 3131 59% medical 59% medical benefitbenefit

ChengCheng 30 30 60% medical 60% medical benefitbenefit



Patients views of purpose of Phase IPatients views of purpose of Phase I

Anticancer ResponseAnticancer Response 61%61% Toxicity DeterminationToxicity Determination 27%27% CombinationCombination 8% 8%


Meropol Meropol et al.et al. (2003) (2003)

Maximum Benefit of Experimental Maximum Benefit of Experimental TherapyTherapy37% of studies only investigational agents37% of studies only investigational agents

Totally cureTotally cure 39%39% Reduce cancerReduce cancer 26%26% Control cancerControl cancer 30%30% Improve symptomsImprove symptoms 3%3% NothingNothing 2%2%



75% reported that the main reason for 75% reported that the main reason for trials was to improve treatment of future trials was to improve treatment of future patientspatients

71% there may not be direct medical 71% there may not be direct medical benefit to mebenefit to me

48% report treatments and procedures in 48% report treatments and procedures in the trial are standard for their cancerthe trial are standard for their cancer

ElizabethElizabeth

““I know you want me to say that this I know you want me to say that this trial is about safety. But the doctors trial is about safety. But the doctors wouldn’t start the trial without wouldn’t start the trial without hoping they could prove the drug hoping they could prove the drug would be effective in stopping would be effective in stopping cancer in future trials.”cancer in future trials.”

DisclosureDisclosure Are Phase I informed consent Are Phase I informed consent

documents distortive?documents distortive?

UnderstandingUnderstanding Do terminally ill patients understand Do terminally ill patients understand

information about Phase I research?information about Phase I research?

VoluntarinessVoluntariness Are terminally ill patients able to Are terminally ill patients able to

choose freely?choose freely?


The Ethical Concern Raised The Ethical Concern Raised about Voluntarinessabout Voluntariness

Some critics argue that terminally Some critics argue that terminally ill patients not only have clouded ill patients not only have clouded understanding and are not acting understanding and are not acting voluntarily but under compulsion voluntarily but under compulsion by their impending death.by their impending death.

No data on the voluntariness of the No data on the voluntariness of the informed consent process in phase I informed consent process in phase I cancer studiescancer studies

VoluntarinessVoluntariness

We Don’t Ignore Other We Don’t Ignore Other Decisions People Make at Decisions People Make at

the End of Lifethe End of Life Just facing terminal illness does not Just facing terminal illness does not

invalidate people’s decisionsinvalidate people’s decisions We accept estate wills and DNR We accept estate wills and DNR

requests made by terminally ill patients requests made by terminally ill patients as genuineas genuine

We do not reject the consent of life-We do not reject the consent of life-saving organ transplants as prima facie saving organ transplants as prima facie invalid because they are made by invalid because they are made by terminally ill patients who cannot think terminally ill patients who cannot think clearlyclearly

Cannot Label Everyone with Cannot Label Everyone with Advanced Cancer as Advanced Cancer as

IncompetentIncompetent There will be some people with There will be some people with

advanced cancer who are able to advanced cancer who are able to and do make rational , reasonable, and do make rational , reasonable, informed decisions and some who informed decisions and some who can’t just like those without can’t just like those without advanced canceradvanced cancer

But cannot conclude that all patients But cannot conclude that all patients with advanced cancer are unable to with advanced cancer are unable to give informed consent give informed consent

SummarySummary

Risk-Benefit ratio is not unfavorableRisk-Benefit ratio is not unfavorable There are more benefits than ascribed by There are more benefits than ascribed by

criticscritics The Risk-Benefit ratio is not clearly worse The Risk-Benefit ratio is not clearly worse

than some FDA approved therapy than some FDA approved therapy Patients perspective should be taken into Patients perspective should be taken into

account when deciding about risk-benefit account when deciding about risk-benefit ratiosratios

Data does not suggest that consent is Data does not suggest that consent is uninformeduninformed

ethics of phase i oncology trials

Documents

todays phase

phase isome notable

future efficacy studies

important response data

cancer drug research

drugs fromthe metaanalyses

drugs andreviewing

metaanalyses had30